Optically pure 1,3-dioxenones, methods for preparing same and use thereof

ABSTRACT

Disclosed are new 1,3-dioxenones having the formulae ##STR1## in an optically pure state, a process for preparing same and the use thereof.

This is a division of application Ser. No. 350,077filed May 10, 1989, now U.S. Pat. No. 5,026,877, which is a division of Ser. No. 076,417, now patented, U.S. Pat. No. 4,864,037.

The present invention relates to optically pure 1,3-dioxenones having the formulae Ia and Ib and the preparation thereof by acetalization of an acetoacetic acid derivative with an optically active carbonyl component and separation of the product mixture by chromatography or distillation or by crystallization.

Y. Oikawa, K. Sugano, O. Yonemitsu, J. Org. Chem. 43, 2087 (1978) already described the synthesis of the racemic mixture of a 1,3-dioxenone of the formula I (Ia═Ib; R₁ ═R₂ ═CH₃) starting from a 1, 3-dioxanedione. An accumulation or synthesis in a pure state of optically active 1,3-dioxenones of the formulae Ia and/or Ib so far has not been described.

Thus, the invention relates to 1,3-dioxenones of the formulae Ia and Ib in their optically active forms and at the same time in an optically pure state ##STR2## wherein R₁, R₂, R₃ and R₄ may be H, C₁ -C₈ -alkyl, C₁ -C₈ -alkoxyl, and hydroxylated and/or carbonylated C₁ -C₈ -alkyl groups which may contain one or more double bond(s), may further be aryl groups, Cl, Br, F and CN as well as COOH and/or the esters thereof and --C(═O)--R [wherein R may be H, C₁ -C₈ -alkyl, C₁ -C₈ -alkoxyl, and a hydroxylated and/or carbonylated C₁ -C₈ -alkyl group which may contain one or more double bond(s) and/or triple bond(s) and or aryl groups]. R₁ and R₂ may also represent a ring of the size C₂ -C₁₂ which in turn may also be C₁ -C₈ -alkylated, alkoxylated, hydroxylated and/or carbonylated and/or arylated. Said ring may also contain one or more double bond(s) and/or triple bond(s). In addition to ring carbon atoms there may also be present hetero atoms such as nitrogen, oxygen, sulfur, boron. Furthermore, R₁ must always be different from R₂ . R₁ and R₂ may be parts of a common ring which ring should bear at least one center of chirality.

The invention further relates to a method for preparing optically pure 1,3-dioxenones having the formulae Ia and Ib wherein R₁, R₂, R₃ and R₄ are defined as above, which method is characterized in that a cyclic or acyclic carbonyl compound having the formula III ##STR3## which is optically active and wherein R₁ and R₂ are defined as above are acetalized with an acetoacetic acid derivative having the formula IV ##STR4## wherein R₃ and R₄ are defined as above, and the obtained condensation products, viz. the 1,3-dioxenones of the formulae Ia and Ib, are separated by chromatography and/or distillation and/or preferably by crystallization. R₅ is to be selected so that --COR₅ in the formula IV is a conventional carboxylic acid derivative or the acid itself (R₅ ═OH).

The C₁ -C₈ -alkyl, C₁ -C₈ -alkoxyl, and hydroxylated and/or carbonylated C₁ -C₈ -alkyl groups may include straight-chain and branched alkyl groups. R₁ and R₂ especially may also be parts of a common ring.

Thus, examples for the C₁ -C₈ groups in R₁ to R₄ include: H, methyl, ethyl, i- and n-propyl, n-but-1-yl, n-but-2-yl, isobutyl, t-butyl; among the C₄ -C₈ -alkyl, alkoxyl and hydroxylated and carbonylated alkyl groups, the n-alkyl groups as well as the 2- and 3-methylalkyl groups are preferred. The double bonds, triple bonds, OH groups and C═O groups in the C₂ -C₈ -alkyl, alkoxyl and hydroxylated and carbonylated alkyl groups are preferably in the 1-, 2- and 3-positions. The aryl groups in R₁ to R₄ are preferred to be substituted phenyl, naphthyl or anthracyl nuclei which may also bear hetero atoms, preferably nitrogen (for example, pyridine derivatives). In the case that R₁ and R₂ are parts of a common ring, said ring may be derived from (+)-camphor (carbonyl component III=camphor) or preferably from (-)-menthone carbonyl component III=menthone). Examples for R₅ include OH, Cl, methoxy, i- and n-propoxy, t-butoxy, phenoxy and acetoyl.

The object of the present invention has been attained by reacting an optically carbonyl component of the formula III with an acetoacetic acid derivative of the formula IV to form Ia and Ib (acetalization) and separating Ia and Ib from each other by chromatography, distillation or, preferably, by crystallization. It was surprisingly found that both forms, Ia and Ib, are formed and can be readily separated by crystallization and chromatography to form the pure compounds. As the carbonyl component III, (-)-menthone was found to be particularly suitable.

Furthermore it was suprisingly found that the formation ratio of Ia and Ib in the course of the acetalization may be varied by the selection of the acid to be employed and the reaction temperature. Thus, by using sulfuric acid, the Ia/Ib ratio obtained is 6:1 at a temperature of -5° C. and 1:1 at a temperature of 10° C. By using p-toluenesulfonic acid the Ia/Ib ratio obtained is 4:1 at a temperature of -5° C. The acetalization of III+IV to form Ia+Ib may be effected in the presence as well as in the absence of a solvent.

1,3-Dioxenones are starting compounds for the syntheses of (+)- and (-)-Grandisols (pheromones) [M. Demuth, A. Palomer, H.-D. Sluma, A. K. Dey, C. Kruger and Y.-H. Tsay, Angew. Chem. Int. Ed. Engl. 25, 1117 (1986)].

The invention is further illustrated by the following examples.

EXAMPLES 1 AND 2 ##STR5##

R₃ ═CH₃ ; R₄ ═H; R₅ ═O-t-butyl.

EXAMPLE 1

31 g of (-)-menthone were mixed with 32 g of (IV) (R₃ ═CH₃ ; R₄ ═H; R₅ ═O-t-butyl; t-butyl acetoacetate) and 68 g of acetic anhydride. 10 ml of sulfuric acid were dropwise added at -5° C., and the mixture was stirred for 48 h. Then the mixture was added to 1 liter of a stirred cold 10% aqueous sodium carbonate solution, and the resulting mixture was extracted with ether. The organic phase contained Ia and Ib in a ratio of 6:1. Purification of the residue on silica gel (solvent: n-hexane+ethyl acetate-9:1) yielded 7 g of Ia (R₁, R₂ =parts of the menthone backbone; R₃ ═CH₃, R₄ ═H) and 1.2 g of Ib (R₁, R₂ =parts of the menthone backbone; R₃ ═CH₃, R₄ ═H). Total yield: 34%.

EXAMPLE 2

60 g of (-)-menthone were mixed with 61 g of (IV) (R₃ ═CH₃ ; R₄ ═H; R₅ ═O-t-butyl; t-butyl acetoacetate) and 120 ml of acetic anhydride. 40 ml of sulfuric acid were dropwise added at -10° C., and the mixture was stirred for 2 h at room temperature. Then the mixture was extracted two times with 500 ml portions of aqueous sodium hydrogencarbonate solution (10%) and with ether. The organic phase contained Ia and Ib in a ratio of 1:1. The organic phase was concentrated by evaporation, and residue was taken up in n-hexane. 7.5 g of Ib (R₁, R₂ =parts of the menthone backbone; R₃ ═CH₃, R₄ ═H) crystallized. The filtrate contained 10 g of Ia (contaminated by a small proportion of Ib) which was subsequently purified on silica gel (solvent: n-hexane+ethyl acetate-9:1). Thereby, 8 g of purest Ia (R₁, R₂ =parts of the menthone backbone; R₃ ═CH₃, R₄ ═H) were eluated.

Spectroscopic Data

Ia (Examples 1 and 2):

IR: γ=1710, 1225, 1180, 1140, 1075 cm⁻¹.

MS: m/z 238 (M⁺), 196, 154, 139, 112, 69, 55, 41.

¹ H-NMR: δ=5.12 (s, 1H), 2.56 (ddd, J=2.5, 3.5, 13.5 Hz, 1H), 2.17 (dh, J=2.5, 7 Hz, 1H), 1.94 (s, 3H), 1.42-1.80 (m, 6H), 0.97 (t, J=13 Hz, 1H), 0.91 (d, J=7 Hz, 3H), 0.87 (d, J=7 Hz, 3H), 0.84 (d, J=6 Hz, 3H).

¹³ C-NMR: δ=168.6, 161.0, 109.7, 93.1, 49.3, 40.9, 34.0, 28.5, 25.5, 23.1, 22.2, 21.5, 20.0, 18.5.

[α]_(D) =-27.4° (c=0.48, chloroform).

Ib (Examples 1 and 2):

Melting point: 49° C.

IR: γ=1710, 1630, 1275, 1075 cm⁻¹.

MS: m/z 238 (M⁺).

¹ H-NMR: δ=5.16 (s, 1H), 2.57 (ddd, J=1, 2, 14 Hz, 1H), 2.29 (gh, J=1, 7 Hz, 1H), 1.95 (s, 3H), 1.74 (dm, J=13 Hz, 1H), 1.65 (m, 1H), 1.44-1.56 (m, 4H), 1.05 (t, J=13 Hz, 1H), 0.9 (d, J=7 Hz, 3H), 0.85 (d, J=7 Hz, 3H), 0.83 (d, J=7 Hz, 3H).

¹³ C-NMR: δ=168.0, 161.5, 109.5, 93.6, 49.1, 40.3, 33.8, 29.6, 25.1, 23.0, 21.7, 21.5, 20.0, 18.1.

[α]_(D) =-22.5° (c=0.4, chloroform).

EXAMPLE 3

III=(-)-methone; R₁ and R₂ see Examples 1 and 2; R₃ ═CH₃ ; R₄ ═COO-t-butyl; R₅ ═O-t-butyl.

EXAMPLE 3

60 g of (-)-methone were mixed with 70 g of (IV) (R₃ ═CH₃ ; R₄ ═R₅ ═O-t-butyl) and 120 ml of acetic anhydride. 40 ml of sulfuric acid were dropwise added at -10° C., and the mixture was stirred for 10 h. The procedure was continued according to Example 1, and Ia (R₁, R₂ =parts of the methone backbone; R₃ ═CH₃, R₄ ═COO-t-butyl) and Ib (R₁, R₂ =parts of the methone backbone; R₃ ═CH₃, R₄ ═COO-t-butyl) were obtained at a ratio of 6:1 in comparable yields.

Spectroscopic Data

Ia (Example 3):

IR: γ=1710, 1695, 1630, 1225, 1180, 1140, 1065 cm⁻¹.

MS: m/z 338 (M⁺).

¹ H-NMR: δ=2.5 (ddd, J=3, 3.5, 13.5 Hz, 1H), 2.17 (dh, J=3, 7.5 Hz, 1H), 1.94 (s, 3H), 1.4-1.85 (m, 6H), 0.99 (t, J=13 Hz, 1H), 0.9 (d, J=7.5 Hz, 3H), 0.85 (d, J=7.5 Hz, 3H), 0.82 (d, J=6 Hz, 3H), 0.78 (s, 9H).

[α]_(D) =-37.4° (c=0.44, chloroform).

Ib (Example 3):

IR: γ=1710, 1700, 1625, 1270, 1095 cm⁻¹.

MS: m/z 338 (M⁺).

¹ H-NMR: δ=2.55 (ddd, J=1, 2, 12 Hz, 1H), 2.3 (dh, J=1, 7.5 Hz, 1H), 1.92 (s, 3H), 1.75 (dm, J=12 Hz, 1H), 1.65 (m, 1H), 1.5-1.65 (m, 4H), 1.0 (t, J=12 Hz, 1H), 0.9 (d, J=7.5 Hz, 3H), 0.83 (d, J=7.5 Hz, 3H), 0.81 (d, J=7.5 Hz, 3H), 0.78 (s, 9H).

[α]_(D) =-32.6° (c=0.5, chloroform).

EXAMPLE 4 ##STR6##

R₃ ═CH₃ ; R₄ ═H; R₅ ═O-t-butyl.

EXAMPLE 4

45 g of (-)-8-phenylmethone were mixed with 30 g of (IV) (R₃ ═CH₃ ; R₄ ═H, R₅ ═O-t-butyl; t-butyl acetoacetate), 120 ml of acetic anhydride and 200 ml of dibutylether. 15 ml of sulfuric acid were dropwise added at -10° C., and the mixture was stirred for 4 h at room temperature. The procedure was continued according to Example 2, and Ia (R₁, R₂ =parts of the 8-phenylmethone backbone; R₃ ═CH₃, R₄ ═H) and Ib (R₁, R₂ =parts of the 8-phenylmethone backbone; R₃ ═CH₃, R₄ ═H) were obtained at a ratio of 1:1 in comparable yields.

EXAMPLE 5 ##STR7##

R₃ ═CH₂ CH₃ ; R₄ ═Cl; R₅ ═OCH₃.

EXAMPLE 5

27 g of (+)-2,3-O-isopropylidene-glycerinaldehyde together with 28 g of (IV) (R₃ ═CH₂ CH₃ ; R₄ ═Cl, R₅ ═OCH₃) were dissolved in 200 ml of dichloromethane. 10 g of p-toluenesulfonic acid were added at -30° C., and the mixture was stirred at that temperature for 15 h. The procedure was continued according to Example 1, and Ia (R₁ ═H, R₂ =parts of the 2,3-O-isopropylidene-glycerinaldehyde backbone; R₃═CH₂ CH₃, R₄ ═Cl) and Ib (R₂ ═H, R₁ =parts of the 2,3-O-isopropylidene-glycerinaldehyde backbone; R₃ ═CH₂ CH₃, R₄ ═Cl) were obtained at a ratio of 4:1 in comparable yields.

EXAMPLE 6

III=(+)-2,3-O-isopropylidene-glycerinaldehyde; R₁ and R₂ see Example 5 R₃ ═CH₂ CH₃ ; R₄ ═(C═O)--C.tbd.C--C₄ H₉, R₅ ═H.

EXAMPLE 6

54 g of (+)-2,3-O-isopropylidene-glycerinaldehyde together with 35 g of (IV) (R₃ ═CH₂ CH₃ ; R₄ ═(C═O)--C.tbd.C--C₄ H₉, R₅ ═H) were dissolved in 500 ml of tetrahydrofurane. 15 g of p-toluenesulfonic acid were added at -5° C., and the mixture was stirred at that temperature for 7 h. The procedure was continued according to Example 1, and Ia (R₁ ═H, R₂ =parts of the 2,3-O-isopropylidene-glycerinaldehyde backbone; R₃ ═CH₂ CH₃, R₄ ═(C═O)--C.tbd.C--C₄ H₉, R₅ ═H) and Ib (R₂ ═H, R₁ =parts of the 2,3-O-isopropylidene-glycerinaldehyde backbone; R₃ ═CH₂ CH₃, R₄ ═(C═O)--C.tbd.C--C₄ H₉, R₅ ═H) were obtained at a ratio of 4:1 in comparable yields.

EXAMPLE 7 ##STR8##

R₃ ═CH₂ CH₂ (-2-pyridyl) or CH₂ CH₂ (3-indolyl), R₄ ═CH₂ --C(CH₃)═CH₂ ; R₅ ═O(CO)CH₃.

EXAMPLE 7

50 g of (+)-pulegone together with 105 g of (IV) (R₃ ═CH₂ CH₂ (-2-pyridyl) or CH₂ CH₂ (3-indolyl), R₄ ═CH₂ --C(CH₃)═CH₂ ; R₅ ═O(CO)CH₃) were dissolved in 100 ml of acetic anhydride and 500 ml of tetrahydrofurane. 20 g of hydrochloric acid were added at -20° C., and the mixture was stirred at that temperature for 15 h. The procedure was continued according to Example 1, and Ia {R₁, R₂ =parts of the pulegone backbone; R₃ ═CH₂ CH₂ (-2-pyridyl) or CH₂ CH₂ (3-indolyl), R₄ ═CH₂ --C(CH₃)═CH₂ } and Ib {R₁, R₂ =parts of the pulegone backbone; R₃ ═CH₂ CH₂ (-2-pyridyl) or CH₂ CH₂ (3-indolyl), R₄ ═CH₂ --C(CH₃)═CH₂ } were obtained at a ratio of 5.5:1 in comparable yields. 

We claim:
 1. An optically pure 1,3-dioxenone of the formula Ia or Ib ##STR9## wherein R₁ and R₂ together form a ring of up to 12 atoms having at least one center of chirality and substituted by at least one member selected from the group consisting of C₁ -C₈ -alkyl, C₁ -C₈ -alkoxy, hydroxy, carboxy, phenyl, naphthyl, anthracyl and pyridyl, which ring may include at least one hetero atom selected from the group consisting of nitrogen, oxygen, sulfur and boron,R₃ and R₄ are each independently selected from the group consisting of H, C₁ -C₈ -alkyl, C₁ -C₈ -alkoxy, hydroxy-C₁ -C₈ -alkyl, carboxy-C₁ -C₈ -alkyl, C₁ -C₈ -alkenyl, C₁ -C₈ -alkenoxy, hydroxy-C₁ -C₈ -alkenyl, carboxy-C₁ -C₈ -alkenyl, phenyl, naphthyl, anthracyl, pyridyl, Cl, Br, F, CN, COOH or --C(═O)--R, and R is H, C₁ -C₈ -alkyl, C₁ -C₈ -alkoxy, hydroxy-C₁ -C₈ -alkyl, carboxy-C₁ -C₈ -alkyl, C₁ -C₈ -alkenyl, C₁ -C₈ -alkenoxy, hydroxy-C₁ -C₈ -alkenyl, carboxy-C₁ -C₈ -alkenyl or phenyl.
 2. An optically pure 1,3-dioxenone according to claim 1, in whichR₄ is selected from the group consisting of C₁ -C₈ -alkyl, C₁ -C₈ -alkoxy, hydroxy-C₁ -C₈ -alkyl, C₁ -C₈ -alkenyl, C₁ -C₈ -alkenoxy, hydroxy-C₁ -C₈ -alkenyl, carboxy-C₁ -C₈ -alkenyl, phenyl, naphthyl, anthracyl, pyridyl, Cl, Br, F, CN, COOH or --C(═O)--R. 